CN105833420A - Multidirectional mucosal delivery devices and methods of use - Google Patents

Abstract

The present invention relates to a pharmaceutical dosage form for transmucosal delivery of an active agent to two or more mucosal surfaces. The dosage form is presented as a transmucosal delivery device. The devices of the invention may include at least two mucoadhesive surfaces. The devices may further include an intermediate layer disposed between the mucoadhesive layers. The pharmaceutical can be incorporated in any one or all of the mucoadhesive layers or the intermediate layer. Upon application, the device adheres to at least two surfaces, providing transmucosal delivery of the drug to at least two surfaces.

Description

Multidirectional mucosal delivery devices and using method

The application is filing date on June 23rd, 2009, Application No. 200980121458.X, invention entitled " multidirectional Mucosal delivery devices and using method " divisional application of patent application.

Related application

The interests of the U.S. Provisional Patent Application the 61/074,918th of patent application claims submission on June 23rd, 2008 And priority.During disclosure of which is hereby incorporated by reference in their entirety.

Summary of the invention

Disclosed herein is for method and the drug delivery device of experimenter's transmucosal delivery activating agent and manufacture these The method of device.It is not intended to be limited to any specific theory, it is believed that the drug delivery device of the present invention, same by each device Shi Shixian at least two attachment sites and medicine deliver, it is allowed to improve the load of activating agent, and in some embodiments, permit Permitted to improve the absorption of activating agent in experimenter.Such as, the illustrative drug delivery apparatus of the present invention can include that at least two is glued Film adhesive surface, so that activating agent strides across two mucomembranous surfaces and is absorbed simultaneously.

There is provided herein by using tested to these needs of thin and flexible drug delivery device to the experimenter needed The method of person's transmucosal delivery activating agent.This device comprise for the first mucosal adhesive surface of transmucosal delivery activating agent and with The second mucosal adhesive surface for transmucosal delivery activating agent of the first mucosal adhesive surface opposite.This device also includes mixing Activating agent therein.First and second mucosal adhesive surfaces are formed by least one thin and flexible mucosal adhesive thin layer.? When using, the activating agent of effective dose delivers to experimenter.Two mucosal adhesive surfaces are made into transmucosal delivery activating agent.Spy In other fixed embodiments, this device is biological erodable (bioerodable).Such as, this device can be in the oral cavity Ablation.

In some embodiments, this device is included in the first and second mucosas on the opposite side of single mucosal adhesive layer Adhesive surface.That is, the first and second mucosal adhesive surfaces are formed by single mucosal adhesive layer.In other embodiments, this dress Putting the multi-layered devices being to include at least two mucosal adhesive layer, wherein the first and second mucosal adhesive surfaces are by least the first and Two thin and flexible mucosal adhesive thin layers are formed.There is also wherein the first and second mucosal adhesive surfaces outermost at two Some embodiment on opposite flank.

In some embodiments, this device comprises at least one intermediate layer.Such as, there are two thin and flexible mucosas The device of adhering film layer can have the intermediate layer being placed between two mucosal adhesive thin layers, so that mucosal adhesive thin film Two mucosal adhesive surfaces of layer are relative to each other.

In some embodiments, this device also comprises anti-abuse substrate and the antagonist combined with anti-abuse substrate, Thus stop the abuse of activating agent.In some embodiments, intermediate layer includes anti-abuse substrate and ties mutually with anti-abuse substrate The antagonist closed, so that antagonist basically can not utilize by through mucous membrane.In some embodiments, anti-abuse substrate is placed in Between one mucosal adhesive layer and the second mucosal adhesive layer.In some embodiments, the antagonist of anti-abuse substrate is encapsulated in dress In putting.In some embodiments, in antagonist is encapsulated at least one mucosal adhesive layer.In some embodiments, antagonist Microencapsulation in a device, as in intermediate layer or any one mucosal adhesive layer.

In some embodiments, this device also includes the intermediate layer being placed between two mucosal adhesive layers or surface, its In, intermediate layer is to close for activating agent.In some embodiments, intermediate layer be close so that mix first and/ Or the activating agent that second in mucosal adhesive layer is not diffused into another layer from this layer.Confining bed stops activating agent to glue from the first mucosa Attached layer to the second mucosal adhesive layer diffusion or spreads to the first mucosal adhesive layer from the second mucosal adhesive layer.At some embodiments In, anti-abuse substrate is impregnated in intermediate layer.In other embodiments, anti-abuse substrate is mixed in intermediate layer by encapsulating.

Additionally provide wherein activating agent be impregnated in the first mucosal adhesive layer or surface, the second mucosal adhesive layer or surface or Other embodiments in any combination on layer or surface.In some embodiments, it can be envisaged that and regulation activating agent is permissible It it is the medicine that can abuse.Such as, activating agent can be opioid drug.Suitably opioid drug includes buprenorphine, sweet smell too Buddhist nun etc..

In other embodiments, the device used in the above-mentioned methods include anti-abuse substrate and with anti-abuse substrate phase In conjunction with antagonist, thus stop the abuse of activating agent.Antagonist can include naloxone.In some embodiments, tested Person experiences the withdrawal symptom of moderate.

This method also includes that wherein activating agent transmucosal delivery is to the embodiment of two or more mucomembranous surfaces.Other are real The mode of executing provides or sequentially to be transmitted to mucomembranous surface simultaneously.

Some embodiments provide the device used by applying this device to the mucomembranous cavity of experimenter to experimenter, So that delivery apparatus adheres at least two surface of mucomembranous cavity and activating agent strides across at least two diffusion into the surface of mucomembranous cavity.

In some embodiments, the activating agent of effective dose delivers to experimenter in less than about 1 hour.Real at other Executing in mode, Delivery time is less than about 45 minutes, or less than about 30 minutes, or less than about 20 minutes, or less than about 15 minutes.In some embodiments, effective time of staying is of about 20 minutes or about 30 minutes.

This method includes some embodiment so that experimenter does not suffers from significantly feeling sick when using this device.

In some embodiments, the onset of pain relief less than about 1.0 hours or 0.5 hour, 0.25 hour or Realize in 0.1 hour.

In some embodiments, this device directly delivers fentanyl to mucomembranous surface, to obtain less than about 1.5 hours T_max.In other embodiments, T_maxFor less than about 1 hour, less than about 0.5 hour or less than about 0.25 hour.

Some embodiments provide the device of load about 800 μ g fentanyls.In some embodiments, C_maxIt is of about 1.84ng/mL, 2ng/mL, 2.2ng/mL or 3ng/mL or 4ng/mL or 5.95ng/mL or 5.47ng/mL.Additionally provide Wherein AUC_0-24Be of about 10hr-ng/mL, 12.50hr-ng/mL, 20.22hr-ng/mL, 34.89hr-ng/mL or The embodiment of 32.63hr-ng/mL or bigger.

Also provide during wherein activating agent is fentanyl and device load fentanyl more than about 30%, 40%, 50%, 60%, 70% or 75% embodiment becoming bioavailable when mucosal administration.

In other embodiments, the activating agent in device is buprenorphine, and measures in the range of about 0.1mg to about 60mg.In some embodiments, T_maxLess than about 100 minutes, and in other embodiments, T_maxLess than about 80 points Clock, less than about 60 minutes, less than about 30 minutes or less than about 20 minutes.Some embodiments provide about 30%, 40%, the bioavailability of the buprenorphine of 50%, 60% or 70%.

In some embodiments, the device used in the above-mentioned methods contains the buprenorphine of about 16mg, and provides The C of about 5.95ng/mL or 8.0ng/mL_max.In some other embodiments, when device comprises the buprenorphine of 8mg, C_maxIt is of about 3.0ng/mL or about 4.5ng/mL.When device comprises the buprenorphine of about 4mg, some embodiment carries For about 1.84ng/mL or the C of about 2.5ng/mL_max。

Some additive methods are also provided herein, for by using any device disclosed herein treatment for some Activating agent (such as, opioid drug) addiction.

In some other embodiment, it is provided that for the method treating pain.In some embodiments, pain is quick-fried The cancer pain of the property sent out.

In some embodiments, said method with a unit dose to the activating agent of tested delivery effective dose.

Brief Description Of Drawings

Fig. 1 is the sketch of exemplary bilateral mucosa adhesive pharmaceutical delivery apparatus, and it has single thin and flexible gluing Film adhering film layer (10), wherein end face (30) and bottom surface (40) can mucoadhesive.

Fig. 2 is the sketch of exemplary double-deck bilateral mucoadhesive device, and it has two mucosal adhesive layers (10 and 20), Wherein end face (30) and bottom surface (40) can mucoadhesive.

Fig. 3 is the sketch of exemplary three layer bilateral mucoadhesive device, and it has two outermost mucosal adhesive layers (10 and 20), wherein, the two outermost layer has relative mucosal adhesive surface (30 and 40).End face and bottom surface can adhere to Film.Intermediate layer (50) can comprise naloxone.

Detailed Description Of The Invention

In order to more understand and describe claimed subject matter concisely, following definition is by the meaning to term used herein Justice provides and instructs.

Unless otherwise noted, as used herein, article " (a and an) " refers to " one or more " or " at least one ".That is, Any key element of the present invention referred to by indefinite article " (a and an) " does not excludes the presence of the probability of more than one this key element.

The most interchangeable term " medicine that can abuse " or " medicine " refer to cause abuse, life-time service Height endurability and/or chemistry or any pharmaceutically active substances of physical dependence or reagent.The medicine that can abuse include but not It is limited to the medicine treating pain, such as opioid analgesic and opioid or opiate.

Term as used herein " antagonist " refers to cause activating agent can not produce pharmacological action, suppress special receptor The function of agonist (medicine as abused) or produce a class material of contrary pharmacological action.It is not intended limited to any spy Different theoretical, it is believed that antagonist generally will not change the chemical constitution of the medicine self that can abuse, but at least partially through right The effect of experimenter and play a role, such as by being combined and hinder the effect of agonist with receptor.Antagonist can be with agonist Compete specific binding site (competitive antagonist), and/or the binding site different from agonist can be incorporated into and pass through Other binding sites hinder the effect (noncompetitive antaganist) of agonist.The non-limiting example of antagonist includes that opium neutralizes Antibody；Anaesthetic antagonist such as naloxone, naltrexone and nalmefene；Cause irritated agent (dysphoric agent) or stimulant (irritating agent) is such as scopolamine, ketamine, atropine or mustard oil；Or their combination in any.Real in one Executing in mode, antagonist is naloxone or naltrexone.

Term " anti-abuse substrate " is often referred to can the antagonist of Drug abuse substrate in connection.Anti-abuse substrate is to work as Device has when using with abuse route (the most soluble in water to attempt to extract medicine, make dissolving, open, chew and/or cut) The substrate of effect release antagonist, thus such as antagonist is extracted simultaneously and changes or the effect of blocking drugs.But by pre- When determining purpose use, such as, when using with non-abuse route, anti-abuse substrate will not effectively discharge antagonist.Such as, antagonist Then be maintained in substrate and be delivered to it and be difficult to absorbed gastrointestinal tract, therefore by mucosa and/or gastrointestinal tract systemic delivery Any amount of antagonist will not significantly block or change the effect of medicine.

Terms used herein " abuse route " refers to use the most in the intended manner delivery apparatus, such as with non-through mucous membrane Mode or other modes not specified by doctor.In some embodiments, abuse route includes extracting from delivery apparatus Medicine is carried out administered orally or parenterally." non-abuse route " used herein refers to use delivery apparatus, example by predetermined purpose Such as mucosal.In some cases, some drugs can the most not transmucosal delivery, such as by a part for device Dissolving and oral delivery.This it is not intended to or unintentional delivery is not belonging to the use of abuse route.

" treatment " of experimenter used herein include to experimenter use medicine to reach to prevent, to cure, to cure, slow Solve, alleviate, change, remedy, improve, promote, stablize or affect the symptom of disease or disease or disease or disease (as alleviated Pain) purpose.

Term " experimenter " refers to the organism lived, such as people, Canis familiaris L., cat and other mammals.Wrapped in apparatus of the present invention Using of the activating agent contained can be carried out according to the effective dosage for the treatment of and the time period of experimenter.

Activating agent " effective dose " needed for reaching therapeutic effect can change according to various factors, the year of such as experimenter Age, sex and body weight.Scalable therapeutic regimen is to provide optimum therapeutic response.Such as, use the dosage of multiple segmentation every day, or Person correspondingly reduces consumption according to the instruction of emergency in treatment.Similarly, can the effective dose root of antagonist of Drug abuse Changing according to other factor, such as comprised in device can the amount of Drug abuse.

As used herein, the term used in device disclosed herein or in the random layer of device is mixed about activating agent " mix " refer to activating agent be placed in the other parts of transmucosal device, in connection, mixed or otherwise Combination, such as layer or coating in one layer of multi-layered devices or multiple layer or as device exist.It should be understood that mixing, combination Or combination needs not be rule or uniform.

In some aspects, it is provided that for the drug delivery device to the experimenter's transmucosal delivery activating agent needed.Should Device includes that the characteristic with mucosal adhesive is adapted to adhere to the thin and flexible thin film of mucomembranous surface.Such as, thin film Character allow by device being adhered on two or more mucomembranous surfaces of subject oral cavity to experimenter's administering active agents. In some embodiments, this device includes thin fexible film, and it has for striding across the first mucomembranous surface orientation diffusion alive Property agent the first mucosal adhesive surface, with the first mucosal adhesive surface opposite be used for stride across second mucomembranous surface orientation diffusion live Property agent the second mucosal adhesive surface, and at least one mix device activating agent so that exist stride across at least two glue The multi-direction diffusion on film surface.Thin and flexible mucosal adhesive thin film (being described as mucosal adhesive layer the most interchangeably) includes At least two mucosal adhesive surface.First mucosal adhesive surface location and the second mucosal adhesive surface opposite, and allow activating agent Stride across the first mucomembranous surface orientation diffusion that it is adhered to.The the second mucosal adhesive surface adhering to the second mucomembranous surface allows to live Property agent stride across second mucomembranous surface orientation diffusion.

Although in some embodiments, this device includes single mucosal adhesive layer, but in other embodiments, this dress Putting is the device of multilamellar, as having the device of two mucosal adhesive layers.The layout of two mucosal adhesive layers makes device keep two Individual relative mucosal adhesive surface.For example, it is possible to the two of applied in two coats device layers (on the other side), so that two Individual outermost surface is mucosal adhesive.It is also contemplated for: can use known to those skilled in the art for preparing multi-layered devices Any other method.Such as, some laminating method may be used for preparing multi-layered devices.

In other embodiments, this device includes one or more being placed between two outermost layer mucosal adhesive surfaces Intermediate layer.Intermediate layer is designed such as in some embodiments, and it provides stability for device.In other embodiments, Intermediate layer is formed as the confinement barrier stoping activating agent to be diffused into another layer from device layer.Such as, have when this device When having two mucosal adhesive layers, intermediate layer can be placed between two mucosal adhesive layers glues preventing from mixing first and/or second Activating agent in film adhesion layer is diffused into another layer.The intermediate layer closed prevents activating agent from expanding from the first mucosal adhesive layer of device It is scattered to the second mucosal adhesive layer of device.Intermediate layer can also be used for mixing anti-abuse substrate or other activating agent.It is also contemplated for tool There is the multi-layered devices of two or more mucosal adhesive layer.Such as, device may comprise 2 to 10 layers.It is positioned at two outermost mucosal adhesives All layers between Ceng are considered as intermediate layer herein.Therefore, intermediate layer can also be mucosal adhesive layer, and it has and outermost The all identical or different attribute of layer mucosal adhesive layer.

In some embodiments, this device includes two mucosal adhesive layers and two kinds of activating agents, wherein first activating agents It is impregnated in the first mucosal adhesive layer to neutralize the second activating agent and be impregnated in the second mucosal adhesive layer.In some embodiments, should Device includes two mucosal adhesive layers and two kinds of activating agents, and wherein the first activating agent and the second activating agent are all impregnated in the first mucosa Adhesion layer neutralizes the second activating agent and is also impregnated in the second mucosal adhesive layer.Be understood that 0, one or more activating agents can be by It is included in each mucosal adhesive layer of device disclosed herein, as long as at least one of which has at least one activating agent.

In some embodiments, this device includes more than one mucosal adhesive layer, as herein described one or more Intermediate layer, and the single-activity agent mixed in one or more mucosal adhesive layer and/or intermediate layer.In some embodiments, This device includes more than one mucosal adhesive layer, one or more intermediate layers as herein described, and mixes one or more viscous More than one activating agent in film adhesion layer and/or one or more intermediate layer.

In some embodiments, this device includes more than one mucosal adhesive layer as herein described so that device glues It is attached on oral mucosa and gingiva tissue, or any other mucomembranous surface in oral cavity.In some embodiments, this device adheres to To hypoglossis mucous membrane.In some embodiments, such as, this device adheres on interior buccal and gingiva, or interior buccal, oral mucosa With molar Vee formation portion (retromolar trigone).In further embodiment, such as, this device is applied to be subject to Examination person Sublingual, and adhere to tongue and/or the downside of little frenulum (frenulum) and the cavity of resorption face in oral cavity.

In one embodiment, this device includes the opioid drug as activating agent.Some embodiments also provide for There is the opioid drug in any combination mixing layer discussed herein and the device of corresponding antagonist.An embodiment party In formula, antagonist and opioid drug can be impregnated in same mucosal adhesive layer.In another embodiment, antagonist is incorporated Enter in the first mucosal adhesive layer, and opioid drug is impregnated in the second mucosal adhesive layer.Another further embodiment party In formula, antagonist is impregnated in two or more mucosal adhesive layer, and opioid drug is impregnated in one of mucosal adhesive layer.? In further embodiment, opioid drug is impregnated in two or more mucosal adhesive layer, and antagonist is impregnated in mucosa In one of adhesion layer.In one embodiment, opioid drug is impregnated in one or more mucosal adhesive layer, and antagonist It is impregnated in one or more intermediate layer.In another embodiment, antagonist is impregnated in one or more mucosal adhesive layer, It is impregnated in one or more intermediate layer with opioid drug.In further embodiment, opioid drug is impregnated in one In individual or multiple mucosal adhesive layers and one or more intermediate layer, and antagonist is impregnated in any one mucosal adhesive layer or centre In Ceng or be impregnated in any combination in mucosal adhesive layer or intermediate layer.In further embodiment, antagonist is impregnated in In one or more mucosal adhesive layers and one or more intermediate layer, and opioid drug is impregnated in any one mucosal adhesive layer Or in intermediate layer or be impregnated in any combination in mucosal adhesive layer or intermediate layer.As further detailed herein, at this In the embodiment of sample, antagonist can be combined with anti-abuse substrate.In some embodiments, anti-abuse substrate is intermediate layer.? In other embodiments, anti-abuse substrate is distribution encapsulated form of antagonist among the intermediate layer or outermost layer of device.? In some embodiment, mix opioid drug and antagonist so that they can not by peel off (pealing) or any its He separates machinery means.

Device disclosed herein and method generally comprise activating agent.Term " activating agent " refers to the reagent being impregnated in device And generally refer not to the polymer for synthesizing mucomembranous adhesion agent.Activating agent includes any having Biological Attribute of Industrial interested Compound, such as, those have the compound of certain effect in the life process of the organism lived.Activating agent can be organic Or inorganic, monomer or polymer, host organisms is endogenic or be not endogenic, naturally occurring or external synthesis , etc..

Activating agent can include being suitable to through mucous membrane and/or the single medicine of sublingual or drug regimen.Medicine include but The medicine that is not limited to abuse, antagonist, anti-inflammation analgesia medicine, steroidal anti-inflammatory medicine, antihistaminic, local anesthetic, antibacterial, disappear Toxic agent, vasoconstrictor, hemorrhage, chemotherapeutics, antibiotic, keratolytic (keratolytics), cauterant (cauterizing agent), and antiviral drugs, antirheumatic, antihypertensive, bronchodilator, anticholinergic agent, Antimenimic compound, hormone and macromole, peptide, protein, vaccine, 5-hydroxytryptamine antagonist (such as 5-HT3 antagonist), Antianxiety drug, hypnotic, serotonin agonist (such as 5-HT agonist) or migraine product.The usage amount of activating agent depends on In required treatment intensity and the composition of layer, although be preferred, but ingredient accounts for about the 0.001% of installation weight to greatly About 99%, more preferably from about 0.003% are to about 30%, most preferably from about 0.005% to about 20%.

The example of medicine includes but not limited to: acetaminophen, methyl salicylate, salicylic acid monoethylene glycol ester, A Si Woods, mefenamic acid, flufenamic acid, indomethacin, diclofenac, Ciclofenaziae (aiclofenac), diclofenac sodium, Bu Luo Sweet smell, ketoprofen, naproxen, pranoprofen, fenoprofen, sulindac, fenclofenac, clidanac, flurbiprofen, fentiazac, fourth Benzene hydroxy acid, piroxicam, Phenylbutazone, oxyphenbutazone, clofezone, pentazocine, epirizole (mepirizole), hydrochloric acid thiophene draw Meter Te, hydrocortisone, meticortelone (predonisolone), dexamethasone, KENALOG, fluocinolone acetonide, acetic acid hydrogenation can Pine, prednisolone acetate, methylprednisolone (methyipredonisolone), dexamethasone acetate, betamethasone, valeric acid times he Meter Song, flumetasone, fluorometholone, double beclometasone, diphhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine, hydrochloric acid chlorine Benzene that quick (chiorpheniramine hydrochloride), chlorphenamine maleate, antol (Sumitomo), salt love song pyrrole that Quick, promethazine hydrochloride, methdilazine hydrochloride, dibucaine hydrochloride, Di and caine, lidocaine hydrochloride, lignocaine, benzene assistant card Because of, to butylamino benzoic acid 2-(lignocaine) carbethoxy hydrochloride, procaine hydrochloride, tetracaine, tetracaine hydrochloride, hydrochloric acid Chloroprocaine (chioroprocaine hydrochloride), hydrochloric acid Oxyprocaine (oxyprocaine Hydrochloride), mepivacaine, ***e hydrochloride, hydrochloric acid skin piperazine pyrrole caine, dyclonine, dyclonine hydrochloride, sulfur willow Hydrargyrum, phenol, thymol, benzalkonium chloride, benzethonium chloride, chlorhexidine, povidone iodine, cetylpyridinium chloride, eugenol, trimethyl bromination Ammonium, privine, tetrahydrozoline hydrochloride, oxymetazoline hydrochloride, phenylephrine hydrochloride, tramazoline hydrochloride, thrombin, Phytonadione, protamine sulfate, aminocaproic acid, tranexamic acid, carbazochrome, carbazochrome sodium sulfonate (carbaxochrome sodium sulfanate), rutin, Hesperidin, sulfonamide (sulfamine), sulfathiazole, sulphur Amic metadiazine, mafenide (homosulfamine), ganda, sulfasomidine, sulfamethizole, nitrofural, penicillium sp Element, methicillin, oxazacillin, cefalotin, cefaloridine (cefalordin), erythromycin, lincomycin, tetracycline, gold Mycin, oxytetracycline, methacycline, chloromycetin, kanamycin, streptomycin, gentamycin, bacitracin, cycloserine, bigcatkin willow Acid, podophyllin, podolifox, cantharidin, monoxone, silver nitrate, protease inhibitor, thymadine kinase inhibitors (thymadine kinase inhibitor), sugar or glycoprotein synthesis inhibitor, structural protein synthetic inhibitor, adhere to and inhale Attached inhibitor and nucleoside analog (such as acyclovir, penciclovir, valaciclovir, ganciclovir), ondansetron, lattice plast Fine jade and palonosetron, benzene phenodiazineAnalog derivative, midazolam, clonazepam, alprazolam, zolpidem, (+)-Zopiclone (eszopiclone), sumatriptan, Zomitriptan (zolmitriptan), naratriptan, Frova, rizatriptan, Ah Not Qu Tan, eletriptan and prochlorperazine.

In some embodiments, activating agent is the medicine that can abuse.The medicine can abused in some embodiments can To be but not limited to opiate and opioid, such as alfentanil, allylprodine, alphaprodine (aiphaprodine), apomorphine (apornorphine), anileridine, apocodeine, benzylmorphine, bezitramide, fourth Third promise coffee, butorphanol, Clonitazene, codeine, cyclorphan (cyclorphan), cyprenorphine, dihydrodesoxymorphine, the right side Rotation amide, Propoxyphene, dezocine, diampromide, diamorphine ketone (diamorphone), dihydrocodeine, double hydrogen Coffee, dimenoxadol, eptazocine, ethylmorphine, etonitazene, etorphine, fentanyl, fencamfamin, fenethylline, hydrogen can Ketone, Dilauid, methylol morphinan, hydroxypethidine, isomethadone, levomethadone, levophenacylmorphan, levorphanol, ibuprofen are too Buddhist nun, Mazindol, Pethidine, metazocine, methadone, methylmorphine, modafinil, morphine, nalbuphine (nalbuphene), Buddhist nun Can morphine (necomorphine), normethadone, normorphine, opium, oxycodone, oxymorphone, pholcodine, Pu Luofa Many, remifentanil, sufentanil, tramadol, corresponding derivant, physiologically acceptable compound, salt and alkali.Implement at some In mode, activating agent is fentanyl.In some embodiments, activating agent is buprenorphine.

In some embodiments, this device includes the combination of medicine and the antagonist that can abuse.The medicine that can abuse and Antagonist can be any medicine abused well known in the art or antagonist, such as, those described herein.Real at some Executing in mode, this device comprises the medicine (such as opioid drug) and antagonist thereof that can abuse, so that opioid drug is indiscriminate With being prevented from.It is thus possible, for instance, it is intended to from transmucosal device extract for parenteral injection can Drug abuse (such as, by Water or other solvents dissolve partly or entirely the extracting of transmucosal device) illegal use by the common extraction resistance of antagonist Only.Antagonist combines with anti-abuse substrate.Anti-abuse substrate can be but not limited to layer or coating, such as water erodable coating Or hydrolyzable substrate such as ion-exchange polymer, or their combination in any.Therefore, in one embodiment, antagonism Agent does not combines with substrate by primary amount in the way of discharging in mouth.In another embodiment, antagonist is by abundant taste masking.Can By as the method for microencapsulation carries out physically trapping or (stops or suppress mucosa absorption short of money as used by chemical conjugation methods The polymer of anti-agent such as ion-exchange polymer) realize embedding and/or taste masking.It is not intended to be fettered by any particular theory, It is believed that the optimum preparation of specific antagonist can by understanding prevent from abusing required ratio, estimate possible binding mechanism with And the physicochemical property evaluating antagonist determines.In some embodiments, antagonist is encapsulated in enteric polymer, many In sugar, starch or polyacrylate.Microencapsulation can be essentially prevented from antagonist through mucous membrane and absorb, and it is micro-to allow experimenter to swallow The antagonist of capsule encapsulating.The coating of microcapsule can be designed as providing the characteristic postponing release, but when goods or compositions are set to Discharge the most immediately when aqueous environments, such as when dosage form is chewed or is extracted.Postponing release can be in the following manner It is achieved, such as, uses starch or pH dependency hydrating polymer as the coating material of the antagonist of microencapsulation.Example As, starch is easily affected by any enzyme (such as ptyalin) being present in saliva.In some embodiments, antagonist quilt Micro-it be encapsulated in microcapsule or microsphere and be subsequently incorporated in anti-abuse substrate.This microcapsule containing antagonist or microsphere can be by Polymer forms, such as polyacrylate, polysaccharide, starch grain, poly-acetas (polyactate) grain or liposome.Further Embodiment in, microsphere and microcapsule be designed to small intestinal specific part discharge.Can select included in product The amount of antagonist, such as to block any psychopharmacology effect that expection produces when medicine independent parenteral administration.One In a little embodiments, the medicine that can abuse is fentanyl, and antagonist is naloxone.In some embodiments, the medicine can abused Thing is buprenorphine, and antagonist is naloxone.In some embodiments, antagonist is tied with anti-abuse substrate as herein described Close.In some embodiments, the antagonist being combined with anti-abuse substrate does not disturb can the transmucosal delivery of Drug abuse.

Mix the antagonist in anti-abuse substrate and include but not limited to opiate or opioid antagonist, such as, receive Lip river Ketone, naltrexone, nalmefene, nalide, nalmexone, nalorphine, nalbuphine, cyclazocine, levallorphan and their physiology can The salt accepted and solvate.In some embodiments, activating agent is naloxone.In one embodiment, anti-abuse base Matter comprises water-soluble polymer, such as, is similar to those and describes for mucoadhesive and/or backing layer, but be combined with this device Polymer so that antagonist not with significant degree by mucosa absorption.In some embodiments, anti-abuse substrate is layer Coating, such as, the erosion properties coating of water.It is to say, can be beneficial to by the barrier layer of the water-soluble polymer coating of slow ablation Antagonist physically trapping in device (such as, mucosal adhesive layer).It is to say, antagonist can at least partly coat or put In the erosion properties coating of water.The method of microencapsulation and particulate coatings is described in detail the most.At some embodiments In, anti-abuse substrate includes the material for physically trapping.These materials include but not limited to alginate, polyethylene glycol oxide, gather Ethylene glycol, polyactide, PGA, PLGA, poly-epsilon-caprolactone, poe, condensing model and derivative Thing, methylcellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxyethylmethyl-cellulose, hydroxypropyl first Base cellulose, polyacrylic acid and sodium carboxymethyl cellulose, polyvinyl acetate, polyvinyl alcohol, Polyethylene Glycol, poly(ethylene oxide), PEP-101, collagen and derivant, gelatin, albumin, polyamino acid and derivant, polyphosphazene, polysaccharide And derivant, chitin, chitosan bioadhesive polymer, polyacrylic acid, polyvinylpyrrolidone, carboxymethyl cellulose Element sodium and combinations thereof.

In some embodiments, this device includes medicine and the antagonist that can abuse, and it is more independent than the medicine that can abuse Use is less susceptible to produce abuse.Such as, when using with abuse route, the medicine that can abuse is only capable of keeping about 50%, 40%, 30%, 20%, 10%, 5%, 2%, 1% or 0% such as the effect as analgesics.Therefore, when using with abuse route, It is believed that the effect of Drug abuse, such as, addict is produced the ability of " pleasant sensation ", corresponding amount will be lowered, as reduced 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99% or 100%.

When using this device in the way of non-abuse, anti-abuse substrate will not effectively discharge antagonist.It is not intended to be appointed What specific theoretical constraint, it is believed that the antagonist being combined with anti-abuse substrate will not enter whole body with significantly amount by mucosa and follow Ring, because it is washed in gastrointestinal tract, as swallowed.Such as, antagonist can as free antagonist or as coating or with Other modes embed the composition of (such as, by the coating/embedding of ion-exchange polymer as described herein) and are washed in gastrointestinal tract.

Comprise the regular dosage form of opioid drug and antagonist, such as U.S. Patent No. 4,582, No. 384 and U.S. Patent No. Dosage form described in 6,227, No. 384, even if generally also can discharge corresponding together with opioid drug when normal administration Antagonist is in mucosa.This can weaken the activity of opioid drug, and usually needs to increase the drug dose in dosage form so that suffering from Person obtains satisfactory effect.In these conventional dosage forms, with compared with the dosage form of opiate antagonist, bad simultaneous phenomenon occurs Risk also increases.And, when this dosage form is when correctly using, needing will not be right due to the opiate antagonist of release vast scale Experimenter increases pressure further.

In some embodiments, anti-abuse substrate is layer or coating, and for example, at least part is arranged around at antagonist The erosion properties coating of water or layer.In some embodiments, anti-abuse substrate is that hydrolyzable, water is erosion properties or water miscible base Matter, such as ion-exchange polymer.Coating or hydrolyzable substrate can be selected so that it is slower than above-mentioned mucosal adhesive layer Ground dissolves.Can also additionally or alternatively select coating or hydrolyzable substrate, so that its dissolving does not discharges the most slowly and completely Antagonist.

Anti-abuse substrate includes but not limited to: partial cross-linked polyacrylic acid, polycarbophil (polycarbophil), poly- Dimension ketone (providone), cross-linking sodium carboxymethyl cellulose, gelatin, chitosan, AmberliteTM 1RP69, DuoliteTM AP143, AMBERLITETM 1RP64, AMBERLITETM 1RP88 and combinations thereof.In other embodiments, Anti-abuse substrate includes but not limited to: alginate, polyethylene glycol oxide, Polyethylene Glycol, polyactide, PGA, lactide-second is handed over Ester copolymer, poly-epsilon-caprolactone, poe, condensing model and derivant, methylcellulose, ethyl cellulose, hydroxy propyl cellulose Element, hydroxyethyl cellulose, hydroxyethylmethyl-cellulose, hydroxypropyl methyl cellulose, polyacrylic acid and sodium carboxymethyl cellulose, Polyvinyl acetate, polyvinyl alcohol, Polyethylene Glycol, poly(ethylene oxide), PEP-101, collagen and derivative Thing, gelatin, albumin, polyamino acid and derivant, polyphosphazene, polysaccharide and derivant, chitin or chitosan are biological Sticky polymers, polyacrylic acid, polyvinylpyrrolidone, sodium carboxymethyl cellulose and combinations thereof.Be understood that polymer, layer, Coating and hydrolyzable substrate are exemplary, and use the teaching of the disclosure to it is contemplated that other anti-abuse substrate.

In some embodiments, during anti-abuse substrate is impregnated in one or more mucosal adhesive layer and/or intermediate layer.? In some embodiments, when device is multilamellar disk (disc) or thin film, anti-abuse substrate is layer or is impregnated in and is placed in mucosa In intermediate layer between adhesion layer.In some embodiments, anti-abuse substrate is intermediate layer.In some embodiments, anti- Abuse substrate is with the speed ablation slower than one or more mucosal adhesive layers and/or intermediate layer.

Such as, when device dissolves for the purpose of abuse, antagonist and the medicine that can abuse can be with essentially identical Speed discharges.Such as, when antagonist and the medicine dissolution that can abuse are in water, they can be with essentially identical speed release. In other embodiments, the antagonist of release and release the ratio of Drug abuse can be not less than about 1:20.

Mix the antagonist in the device of any embodiment discussed herein basically can not utilize by through mucous membrane.Therefore, The availability not interfering with activating agent used by the through mucous membrane prescription of the device comprising medicine.Phrase " basically can not through mucous membrane profit With " refer to when using with non-abuse route, the available amount of antagonist through mucous membrane in compositions and device does not interferes with can Effect of Drug abuse or affect insignificant.Be not intended to be fettered by any particular theory, it is believed that antagonist be prevented from or Slowing down through mucous membrane and enter body system, but still can utilize (such as swallow or dissolve) by other route of administration, this makes to abuse Medicine effectively can play a role with the form of transmucosal composition, then hinder compositions with abuse route when using Use.That is, it is thus understood that when compositions disclosed herein is abused, antagonist impact can the effect of Drug abuse. Under non-abuse situation, antagonist will not or play a role the most fiddling, such as when being swallowed.At some embodiments In, the antagonist (relative to the weight of the medicine that can abuse) less than about 25% can be passed with non-abuse route (such as through mucous membrane) Send.In other embodiments, the antagonist transmucosal delivery less than about 15%, less than 5%, less than 2% or less than 1%.

It thus provides the method using the bilateral mucoadhesive device for using opioid drug, wherein, this device Forbid, hinder or stop the abuse of the opioid drug mixed.Antagonist as above is when by addition to mucosal administration Method when taking, play the effect of the effect of suppression opioid drug.In some embodiments, it is absorbed into by experimenter The level of the antagonist of systemic circulation is less than about 15 weight %.In some embodiments, the dosage of medicine about 50 to Between about 10mg.

Plasticizer, flavoring agent, coloring agent and preservative can also reside in outermost mucosal adhesive layer or any intermediate layer In.Respective amount can according to medicine or other composition transfer, but generally these compositions account for device gross weight less than 50%, Preferably more than 30%, most preferably not more than 15%.In some embodiments, device includes inactivator.Other embodiment party In formula, device is substantially free of inactivator.Term used herein " inactivator " refers to the medicine that inactivation or crosslinking can be abused Thing is to reduce the compound of the abuse potential of dosage form.The example of inactivator includes polymerizer, light trigger and formalin.Polymerization The example of agent includes diisocyanate, peroxide, imidodicarbonic diamide, glycol, triol, epoxide, cyanoacrylate and purple Outside line activated monomer.

Be included in the device in the range of the disclosure can also optionally comprise pharmaceutically acceptable dissolution velocity regulator, Pharmaceutically acceptable disintegrate auxiliary agent (such as, Polyethylene Glycol, glucosan, polycarbophil, carboxymethyl cellulose or poloxamer), Pharmaceutically acceptable plasticizer, pharmaceutically acceptable coloring agent (such as, FD&C Blue#1), pharmaceutically acceptable screening Photo etching (such as, titanium dioxide), pharmaceutically acceptable antioxidant (such as, tocopheryl acetate), pharmaceutically acceptable system System forms reinforcing agent (such as, polyvinyl alcohol or polyvinylpyrrolidone), pharmaceutically acceptable preservative, spice (such as, sugar Essence and Herba Menthae), nertralizer (such as, sodium hydroxide), buffer agent (such as, sodium dihydrogen phosphate or tertiary sodium phosphate) or a combination thereof.Excellent Selection of land, these compositions individually exist with the amount of about 1% of the final weight less than device, but this amount can be with its of device His composition and change.

Device can also optionally comprise one or more plasticizers, and to soften, to increase toughness, raising is flexible, improve mould Character processed and/or otherwise change the character of device.Plasticizer for embodiment of the present invention may further include, Such as, those have relatively low volatile plasticizer, such as, glycerol, propylene glycol, sorbitol, ethylene glycol, diethylene glycol, three Glycol, propylene glycol, polypropylene glycol, dipropylene glycol, butanediol, diglycerol, Polyethylene Glycol (such as, the PEG of low-molecular-weight), oil Alcohol, spermol, cetearyl alcohol (cetostearyl alcohol) and other have at normal atmospheric pressure higher than about 100 DEG C the alcohol of pharmaceutical grade of boiling point and glycol.Other plasticizer includes, such as, and polysorbate80, triethyl citrate (triethyl titrate), CitroflexA-2 (acetyl triethyl titrate) and tributyl citrate (tributyl titrate).Suitable plasticizer additionally includes, such as, and diethyl phthalate, phthalic acid fourth Ester, butyl glycolate, TG essence and tributyorin.Suitable plasticizer additionally includes, such as, the hydro carbons of pharmaceutical grade, example As, mineral oil (such as, light mineral oil) and vaseline.Other suitable plasticizers include, such as, triglyceride, such as middle chain The triglyceride of triglyceride, soybean oil, safflower oil, Oleum Arachidis hypogaeae semen and other pharmaceutical grade, glycerol three acid of Pegylation Ester, asWith PEG-4 Cera Flava, lanoline, poly(ethylene oxide) (PEO) and other Polyethylene Glycol, Hydrophobic ester such as ethyl oleate, Semen Myristicae isopropyl propionate, isopropyl palmitate, cetyl ester wax, glyceryl monolaurate and single tristearin Acid glyceride.

Can be optionally with one or more disintegrate auxiliary agents to improve disintegration rate and to shorten the stop of apparatus of the present invention Time.The disintegrate auxiliary agent that can be used in the present invention includes, such as, and the hydrophilic compounds being used alone or in combination such as water, methanol, second Alcohol or lower alkyl alcohol (such as isopropanol), acetone, methylethylacetone.Specific disintegrate auxiliary agent includes that those have relatively low waving The disintegrate auxiliary agent of the property sent out, such as, glycerol, propylene glycol and Polyethylene Glycol.

Can be optionally with one or more dissolution velocity regulators to reduce disintegration rate and to extend present invention offer Time of staying of device.Useful dissolution velocity regulator includes, such as, and hydrophobic compound such as heptane and dichloroethanes, two Carboxylic acid or tricarboxylic multi-alkyl ester such as use C₆To C₂₀Alcohols esterification succinic acid and citric acid, aromatic ester such as Benzyl Benzoate Ester, glyceryl triacetate, propylene carbonate and there are other hydrophobic compounds of similarity.These compounds can be used singly or in combination to In device.The time of staying of apparatus of the present invention depends on the ablation speed and each of the water erodable polymer in preparation Concentration.Ablation speed can be adjusted: by having different solubilities characteristic or chemically distinct by such as following methods Polymer (such as hydroxyethyl cellulose, hydroxypropyl cellulose) mix；By using the identical poly-of different molecular magnitude Compound (such as mixing low-molecular-weight and the hydroxyethyl cellulose of intermediate molecular weight)；By use have various different lipotropy value or The excipient of water solubility properties or plasticizer (including essentially insoluble composition)；By using water solublity organic and inorganic salt； By using the cross-linking agent (such as Biformyl) for partial cross-linking and polymer (such as hydroxyethyl cellulose)；Or by shining after processing Penetrating or solidify, this may change the physical state (including its crystallization or phase transformation) of obtained thin film.These strategies can be single Solely or be applied in combination, to change the kinetics of corrosion of device.

In some embodiments, this device is biological erodable.The use of erodable composition makes device at one section Ablation in time, dissolves with nature body fluid or carrier is fallen in corrosion, and medicine still remains in practical site.Unlike binder is non-with other The membranous system that water is erodible, the user of this device need not remove this device after the treatment.User also will not experience at mucomembranous surface Or any substantial sensation of foreign body present in body cavity, because after application, the absorption meeting softening plant of water, and with The passage of time, device slowly dissolves or ablation.In some embodiments, this device ablation in the oral cavity.Real at some Executing in mode, this device does not leave over the residue of any essence, hence helps to reduce experimenter and is likely to be due to use other dresses Put and experience feel sick.Term as used herein " biological erodable " refers to that device can make solid or the semisolid portion of device Point fully degrade by the way of surface ablation, biological ablation and/or body decomposition to such an extent as to its sufficiently small and can be swallowed and System is not caused to stimulate the character of (as felt sick).Body decompose in whole substrate material (such as polymer) with the most homogeneous There is the process of degraded in mode.This cause molecular weight (Ms) reduce and physical property does not occur directly to change, subsequently due to saliva Or water penetrates into the process of device and is faster than device and is converted into saliva or water-soluble form and chipping.Biological ablation or surface disappear Erosion generally occurs when the speed that saliva or water penetrate into material is converted into saliva or water-soluble substances less than material.Biological ablation is led to Often result in material the most thinning, but still remain the integrity of body.It is to be understood that " biological erodable " is to refer to as For overall device, it it not the single composition being necessarily referring to it.Such as, if antagonist is microencapsulation or coating, and with In a kind of device of the rear incorporation present invention, then this microcapsule or coating may or may not be biological erodable, but device is overall Can be biological erodable, thus along with device is swallowed by ablation, complete microcapsule or the antagonist of coating.This may Favourable because device can be intactly delivered to gastrointestinal tract by the antagonist of microcapsule or coating with ablation, i.e. not across Cross mucosa.Term " biological erodable " is intended to include many kinds of substance reset mode perhaps, as enzymatic and the hydrolysis of non-enzymatic, oxygen Change, enzyme assisted oxidation, wear and tear, degrade and/or dissolve.It is not wishing to be bound by any particular theory, it is believed that biological erodable Device is probably favourable, because this device need not remove after a procedure.

Biological erodable material is typically based on their degradation characteristic and selects, and thinks that application-specific provides enough stopping Stay time or functional lifetime.In some devices, functional lifetime is the most suitable at about 1 minute to about 10 hour.At some In embodiment, functional lifetime is of about 20 minutes.In some embodiments, functional lifetime is of about 5 minutes, about 10 points Clock, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 2 hours, about 3 little Time, about 4 hours, about 5 hours or about 10 hours.The all scope sums between scope and numerical value listed by falling into herein Value is all intended to encompass in the embodiment of device disclosed by the invention.Such as, the time of staying be of about 5-about 45 minutes, big About 6-about 53 minutes, about 13-are all contained in the scope of the invention between about 26 minutes etc..Shorter or the longer time is also It is suitable to be probably.

Biological erodable material includes but not limited to that the polymer of condensing model, copolymer and mixture are (as used melted contracting Close, prepared by polymerisation in solution, or uses coupling agent, aromatic acid, aliphatic dibasic acid, aminoacid (such as aspartic acid and paddy ammonia Acid) and copolymer prepare)；Epoxy-terminated polymers and the copolymer of anhydride；Poe；Alpha-hydroxy acid (includes lactic acid, hydroxyl Acetic acid ,-caprolactone, gamma-butyrolacton and-valerolactone) homopolymer and copolymer；The homopolymer of Alpha-hydroxy alkanoate and copolymerization Thing；Polyphosphazene；Polyoxyalkylene, such as alkene (ailcene) are 1-4 carbon, include graft copolymer as homopolymer and copolymer； Poly-(aminoacid), including false poly-(aminoacid)；Poly-dioxanone；Copolymer with Polyethylene Glycol Yu above-mentioned arbitrary substance.

Present invention also offers the device partly formed by thin and flexible mucosal adhesive thin film.This device and thin film are Biological erodable.In some aspects, the preparation of thin film uses water-soluble polymer, and it includes but not limited to, hydroxy ethyl fiber Element, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethylmethyl-cellulose, can partial cross-linked or not cross-link poly-third Olefin(e) acid (PAA), sodium carboxymethyl cellulose (NaCMC) and polyvinylpyrrolidone (PVP) or a combination thereof.Other mucosal adhesives are biological Erodable polymer can be used in the present invention.Mucosal adhesive layer can comprise the polymer that at least one one-tenth film water is erosion properties (" film forming polymer "), and pharmaceutically acceptable polymer (" the biological slime agglomeration of at least one its bioadhesive capability known Compound ").Film forming polymer can comprise hydroxyethyl cellulose alone or in combination, hydroxypropyl cellulose, hydroxypropyl methyl fiber Element, hydroxyethylmethyl-cellulose, polyvinyl alcohol, Polyethylene Glycol, poly(ethylene oxide), PEP-101, collagen Albumen and derivant, gelatin, albumin, polyamino acid and derivant, polyphosphazene, polysaccharide and derivant, a few D prime and deacetylated Chitin.It is preferably film-forming polymers and comprises hydroxyethyl cellulose and hydroxypropyl cellulose.Preferably, in the feelings of hydroxyethyl cellulose Under condition, mean molecule quantity (measures the M estimated from intrinsic viscosity_w) it is 10²To 10⁶, more preferably 10³To 10⁵；And at hydroxy propyl cellulose In the case of element, the mean molecule quantity (M obtained from size exclusion chromatography measurement_w) it is 50x10³To 1.5x10⁶, more preferably 80x10³To 5x10⁵.In adhesion layer, bioadhesive polymer may be with the type of medicine and use with the ratio of film forming polymer Medication amount change.

In some embodiments, intermediate layer is typically by the pharmaceutically acceptable polymer group of the film forming of biological erodable Becoming, it includes but not limited to, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl methyl fiber Element, polyvinyl alcohol, Polyethylene Glycol, poly(ethylene oxide), PEP-101 or a combination thereof.Intermediate layer can be wrapped Containing other water miscible film forming polymers known in the art.The example of floor in U.S. Patent No. 5,800,832 and the 6th, All being described in 159, No. 498, including being suitable for the polymer of this layer, entire contents is incorporated by reference herein.

Assembly of the invention can include various forms.Such as, device can be discoid or thin film.A kind of embodiment party In formula, this device comprises the disk of mucosal adhesive.In a kind of embodiment of methods and apparatus of the present invention, this device is soft The device of property.As solid film or the form of disk, the thickness of apparatus of the present invention can change along with the thickness of each layer.Typically Ground, thickness range is of about 0.005mm-about 3mm, more specifically, about 0.05mm-about 0.5mm.When device is multilamellar Time, the thickness of each layer can change between about the 10% of device gross thickness to about 90%, more specifically, can be at device About the 30% of gross thickness changes between about 60%.

In some embodiments, due to compared with conventional tablet or lozenge device, thinness that this device has and soft Property, therefore produce relatively minimal oral foreign body sense and almost without discomfort.This is for suffering from mucosal inflammation and/or due to other Reason can not cosily use the patient of conventional equipment advantageous particularly.Assembly of the invention is sufficiently small and flexible so that they energy Enough adhere to the noninflammatory region of mucosa and remain effective, i.e. mucosa is not required to carry out erasing by assembly of the invention.

In various different embodiments, assembly of the invention can be to be any form or shape, such as thin slice or disk, Profile or cross section are circular or square etc., as long as this form allows bioactive agent delivery to deliver to experimenter.In some embodiments, Assembly of the invention can be scored, and punching or otherwise labelling are to show certain dosage.

Assembly of the invention is adapted to any mucosa delivery method.In certain embodiments of the present invention, it is provided that with Lower method: wherein, this device is suitable to Buccal administration and/or sublingual administration.In some method, by device is adhered to mucosa The device that the present invention provides is used, to the experimenter needed, in surface.Such as, this device may be used in the method for the treatment of pain, its In, this device is fixed or adhered to any mucomembranous surface of experimenter, and wherein two mucosal adhesive surfaces of device can be by It is fixed on two or more mucomembranous surfaces.The activating agent mixed passes through from device (striding across mucosal adhesive surface) to mucomembranous surface (striding across mucomembranous surface) spreads and transmucosal delivery, and system circulation.Additionally provide and glued by the bilateral mucosa of the application present invention Adsorption device carrys out localised protection to stimulation or impaired tissue to stimulate or the method for impaired mucosal tissue.Activating agent can be with local application And/or systemic administration is to shielded position.

In other respects, it is provided that use any device discussed herein to two or more mucomembranous surface transmucosal deliveries The method of activating agent.Activating agent can simultaneously, substantially simultaneously or sequentially from device be diffused into two or more attachment sites. In some further embodiment, it is simultaneous to the diffusion of sticking point.In some embodiments, the method bag Include the mucomembranous cavity to experimenter and apply device as of the invention described herein, so that doser adheres to mucomembranous cavity extremely Few two surfaces and activating agent stride across at least two diffusion into the surface of mucomembranous cavity.

In some embodiments, the present invention relates to use the side of the pain of the dosage treatment experimenter (such as people) of activating agent Method.The method can use any device of the intended release characteristics with the present invention enumerated herein.Some embodiment party In formula, to experimenter's delivery of active agent in less than about 1 hour, 30 minutes, 20 minutes or 10 minutes.At some embodiments In, systematically delivery of active agent.While not wishing to fettered by single theory, it is believed that owing to multiple mucosal adhesive can be can be used for Multiple sticking points on surface, bilateral mucoadhesive device of the present invention is beneficial to the experimenter's higher biological utilisation to activating agent Degree.It has also been discovered that, the nauseating side effect being generally expected to reduces.Present invention also offers the activity that can load in wherein device The amount of agent is significantly greater than the device of conventional equipment.Such as, the present invention allows up to about 800 μ g, 1000 μ g, 1200 μ g, 1400 μ The citric acid fentanyl of g or 1600 μ g can load in device.During activating agent is the embodiment of buprenorphine wherein, live Property agent load capacity scope is 0.01mg to about 60mg, more preferably 0.1mg to 30mg.

Due to for some opioid drug of pain therapy (including the opioid drug being intended for apparatus of the present invention) Additive, it was found that addiction can be alleviated with the method and apparatus described in the application of the invention.Therefore, the invention provides Any device described in the application of the invention is used opioid drug to experimenter and is treated for opiates described here The method of drug dependence.Such as, it is provided that wherein double-sided adhesive adsorption device includes the embodiment of anti-abuse substrate.Anti-abuse substrate Stop, suppress or prevent abuse property from using.Anti-abuse substrate preparation provides wherein being wrapped of ormal weight by making mucosal administration The opioid drug contained.But, when the experimenter of addiction attempts by such as dissolving this device and injecting the opioid drug of dissolving Means when using the dosage exceeding regulation, anti-abuse substrate makes opioid drug the most invalid.Therefore, potential abuse Can be prevented from, and will be encouraged by the use of prescription.

Dual sticking point also enable devices to mucosal delivery activating agent with less than about 0.5,0.3,0.2 or 0.1 little Time the interior onset reaching pain relief.Bilateral mucoadhesive device of the present invention can dual sticking point make it possible to directly Connect to mucosal delivery activating agent to realize less than about 1.75 hours, less than about 1.5 hours, less than about 1.0 hours, to be less than About 0.5 hour or less than the T of 0.25 hour_max.During device comprises some embodiment of about 800 μ g fentanyls wherein, C_maxIt is of about 2.2ng/mL, 3.2ng/mL or 4.2ng/mL.In some embodiments, AUC_0-24It is of about 10hr-ng/mL Or about 12.5hr-ng/mL or about 15hr-ng/mL.In some embodiments, assembly of the invention is to mucomembranous surface Occur in sticking to about 5 seconds.In some embodiments, assembly of the invention disappeared in about 20 to three ten minutes naturally Erosion and without holding means in position.The example embodiment of the present invention includes that wherein activating agent is that about 0.1mg is to about The device of the buprenorphine of 60mg, so that T_maxLess than about 100 minutes, less than about 80 minutes, less than about 60 minutes, Less than about 30 minutes or less than about 20 minutes.When device contains the buprenorphine of about 16mg, C_maxMay be about 8.0ng/mL.When device comprises 8mg buprenorphine, C_maxMay be about 4.5ng/mL.When device contains the fourth third of about 4mg During promise coffee, C_maxMay be about 2.5ng/mL.

The drug delivery device of the present invention can be prepared by various methods known in the art.Such as, a kind of embodiment party In formula, each composition is dissolved in suitable solvent or solvent combination to prepare solution.The solvent that the present invention uses can comprise water, first Alcohol, ethanol or low-grade alkane alcohol (such as isopropanol), acetone, ethyl acetate, oxolane, dimethyl sulfoxide or dichloromethane, or its Meaning combination.In dry plural layers, the solvent composition of residual can play plasticizer, ablation rate modifier or rate of dissolution The effect of regulator, or some pharmacological benefits can be provided.Required residual solvent may be present in layer.

Then solution is coated on substrate, such as, passes through the known technology casting of this area or be processed as thin film, as adopted Thin film coated, film casting, spin coating or the spraying carried out with applicable substrate.Afterwards by film drying.Drying steps can be in office The baking oven of what type completes；But the amount of residual solvent depends on dry run.When needs multilamellar, these layers can independently become Film is the most laminated together, or can form another tunic on one layer.Multilamellar laminated together or one layer be coated in The thin film obtained on another layer can be cut into arbitrary shape to be applied to mucosal tissue.Some shapes include disc, ellipse Circular, square, rectangle and parallelepiped (parallepiped).

Embodiment

Contemplated embodiments 1: the preparation of exemplary mucoadhesive device

The exemplary mucoadhesive device of the present invention is prepared: add water (about to mixing container by following steps Total formula of 89%, by weight), be then sequentially added into propylene glycol (total formula of about 0.5%, by weight), benzene first (total formula of about 0.06%, by weight), (total formula of about 0.1%, with weight for methyl parahydroxybenzoate for acid sodium Meter) and propyl p-hydroxybenzoate (total formula of about 0.03%, by weight), Vitamin E acetate (about 0.01% Total formula, by weight) and citric acid (total formula of about 0.06%, by weight), iron oxide red (about 0.01% total Formula, by weight) and sodium dihydrogen phosphate (total formula of about 0.04%, by weight).In composition dispersion and/or dissolving After, add 800 μ g citric acid fentanyl (total formula of about 0.9%, by weight), and add heat container to about 120 to 130°F.After dissolving, add polymeric blends [hydroxypropyl cellulose (Klucel EF, about 0.6% always join in container Side, by weight), hydroxyethyl cellulose (Natrosol 250L, total formula of about 1.9%, by weight), polycarbophil (Noveon AAl, total formula of about 0.6% are calculated by weight) and carboxymethyl cellulose (Aqualon 7LF, about Total formula of 5.124%, by weight)], and stir until disperseing.Subsequently, cooling mixing container.Then phosphoric acid can be added Trisodium and sodium hydroxide are to adjust mixture to required pH value.Several hours of blend mixture under vacuo, and at aeroseal Container in preserve until its be used for coating operation.

By on one or more layers casting continuously to suitable surface, such as St.Gobain polyester liner.Above-mentioned preparation Mixture is cast onto interior lining, about 65 DEG C to 95 DEG C at solidify in an oven, and be dried.Identical program can be used Top by other layer casting to initiation layer.Then device is cut (such as, by seam patterning method (kiss-cut Method)), and remove from casting surface.This device is configurable to, and such as, disk, has the rectangular shape of fillet Form.Multiple layers can be bonded together to avoid during applying to mucomembranous surface or be layered afterwards.

Contemplated embodiments 2: the preparation of mucosal adhesive layer

Mucosal adhesive layer is prepared: adding water to mixing container, then order adds propylene glycol, benzoic acid by following steps Sodium, methyl parahydroxybenzoate and propyl p-hydroxybenzoate, Vitamin E acetate, citric acid, iron oxide yellow and biphosphate Sodium.After composition dispersion and/or dissolving, add fentanyl or buprenorphine, add heat container to about 120 to 130 °F.Then to Container adds polymeric blends-hydroxypropyl cellulose (Klucel EF), hydroxyethyl cellulose (Natrosol 250L), gathers Ka Bofei (Noveon AAl) and carboxymethyl cellulose (Aqualon 7LF)], and stir until disperseing.Subsequently, cooling mixing is held Device.As last interpolation step, tertiary sodium phosphate (buffer agent) and sodium hydroxide (pH adjusting agent) can be added to adjust mixing Thing is to required pH value.Mix this mixture the most under vacuo several hours.The mixture of preparation is in air impervious container Preserve, until its preparation is used for coating operation.% (w/w) content of various compositions and any other composition is the most following Form (1,2 and 3) shown in.Table 1 represents the formula 1 of the device with buprenorphine, and table 2 provides joining containing buprenorphine The details of side 2.Table 3 comprises the 3rd formula containing citric acid fentanyl.For formula 1, pH value range is 4.5 to 5.5.For Formula 2, pH scope is 5.0 to 6.0.

Table 1

Table 2

Table 3

Coating processes includes lining in layer casting to St.Gobain polyester continuously.Use scraper cladding process (knife- On-a-blade coating method) casting the first mucosal adhesive layer.Subsequently, if necessary, by the second mucosal adhesive Layer casting is on the first mucosal adhesive layer, in an oven with the temperature-curable of about 65-95 DEG C and be dried.Then cut by seam Cut this product of method cross cutting, and take off from casting surface.

Claims (45)

1. by the method to the experimenter's transmucosal delivery activating agent needed, including:

Using thin and flexible drug delivery device to the experimenter needed, wherein, described drug delivery device includes:

The first mucosal adhesive surface for transmucosal delivery activating agent；

The second mucosal adhesive surface for transmucosal delivery activating agent with the first mucosal adhesive surface opposite；

Mix the activating agent in this device,

Wherein, the first and second mucosal adhesive surfaces are formed by least one thin and flexible mucosal adhesive thin layer；With

Wherein, the activating agent of effective dose is delivered to experimenter.

Method the most according to claim 1, wherein, described device is biological erodable.

Method the most according to claim 1, wherein, described first and second mucosal adhesive surfaces are by single mucosal adhesive layer shape Become.

Method the most according to claim 1, wherein, described first and second mucosal adhesive surfaces by least the first and second thin and Flexible mucosal adhesive thin layer is formed.

Method the most according to claim 4, wherein, described device also includes the centre being placed between two mucosal adhesive surfaces Layer.

Method the most according to claim 5, wherein, described intermediate layer includes anti-abuse substrate and combines with anti-abuse substrate Antagonist, so that antagonist basically can not utilize by through mucous membrane.

Method the most according to claim 5, wherein, described intermediate layer includes the antagonist of microencapsulation.

Method the most according to claim 1, wherein, described mucosal adhesive layer includes the antagonist of microencapsulation.

Method the most according to claim 4, wherein, described intermediate layer is to close for activating agent.

Method the most according to claim 4, wherein, described activating agent is impregnated in the first mucosal adhesive layer and the second mucosal adhesive In Ceng.

11. methods according to claim 1, wherein, described activating agent is the medicine that can abuse.

12. according to the method for aforementioned any one of claim, and wherein, described activating agent is opioid drug.

13. methods according to claim 12, wherein, described activating agent is buprenorphine.

14. methods according to claim 12, wherein, described activating agent is fentanyl.

15. methods according to claim 6, wherein, described antagonist is naloxone.

16. methods according to claim 1, wherein, described activating agent transmucosal delivery is to two or more mucomembranous surfaces.

17. methods according to claim 1, wherein, by being applied to the mucomembranous cavity of experimenter and to experimenter by described device Use described device, so that delivery apparatus adheres at least two surface of mucomembranous cavity and activating agent is crossed over the first mucosa and glued Subordinate list face and the second mucosal adhesive diffusion into the surface.

18. methods according to claim 17, wherein, the activating agent of described effective dose less than in about 1 hour to experimenter Deliver.

19. methods according to claim 17, wherein, the activating agent of described effective dose less than in about 30 minutes to experimenter Deliver.

20. according to the method for any one of claim 1 or 6, and wherein, described experimenter does not occur significantly to feel sick.

21. methods according to claim 14, wherein, the onset of pain relief realizes in less than about 15 minutes.

22. methods according to claim 14, wherein, T_maxFor less than about 1.5 hours.

23. methods according to claim 14, wherein, T_maxFor less than about 1 hour.

24. methods according to claim 14, wherein, T_maxFor less than about 0.5 hour.

25. methods according to claim 14, wherein, T_maxFor less than about 0.25 hour.

26. methods according to claim 14, wherein, described device comprises the fentanyl of about 800 μ g.

27. methods according to claim 26, wherein, C_maxFor more than about 2ng/mL.

28. methods according to claim 26, wherein, C_maxFor more than about 3ng/mL.

29. methods according to claim 26, wherein, C_maxFor more than about 4ng/mL.

30. methods according to claim 26, wherein, the fentanyl more than about 30% is biological available.

31. methods according to claim 26, wherein, the fentanyl more than about 60% is biological available.

32. methods according to claim 26, wherein, the fentanyl more than about 70% is biological available.

33. methods according to claim 13, wherein, described device comprises the buprenorphine of about 0.1mg to about 60mg.

34. according to the method for claim 33, wherein, T_maxLess than about 100 minutes.

35. according to the method for claim 33, wherein, T_maxLess than about 80 minutes.

36. according to the method for claim 33, wherein, T_maxLess than about 60 minutes.

37. according to the method for claim 33, wherein, T_maxLess than about 30 minutes.

38. according to the method for claim 33, wherein, T_maxLess than about 20 minutes.

39. according to the method for claim 33, and wherein, the buprenorphine more than 30% is biological available.

40. according to the method for claim 33, and wherein, the buprenorphine biology more than 50% is available.

41. according to the method for claim 33, and wherein, the buprenorphine biology more than 60% is available.

42. 1 kinds of methods treating addiction, including the method for aforementioned any one of claim.

43. 1 kinds of methods treating pain, including the method by aforementioned any one of claim to experimenter's administering active agents.

44. according to the method for claim 43, and wherein, described pain is fulminant cancer pain.

45. according to the method for aforementioned any one of claim, and wherein, the activating agent of described effective dose is passed with a unit dose Deliver to experimenter.